This invention relates to concentrated aqueous solutions of the antibiotic vancomycin hydrochloride and to a process for the lyophilization thereof.
Vancomycin is described in U.S. Pat. No. 3,067,099. It is a well known antibiotic often prescribed for the treatment of staphylococcal infections, particularly infections caused by methicillin-resistant strains of staphylococcus. Vancomycin is isolated from the fermentation broth in which it is produced. It is formulated for pharmaceutical use as the hydrochloride salt, vancomycin hydrochloride.
Vancomycin hydrochloride is supplied for oral and parenteral use as a dry solid in sterile vials or small bottles. The dry solid form of vancomycin hydrochloride is obtained by lyophilization of aqueous solutions of the hydrochloride. The vancomycin hydrochloride solutions are prepared for lyophilization by treating vancomycin free base in water with hydrochloric acid.
Manufacturing scale lyophilizations are desirably carried out using as small a volume as possible to reduce lyophilization time. In a typical lyophilization technique, an aqueous solution of the active ingredient is lyophilized directly in the container in which it is to be supplied, for example sterile vials or pharmacy bottles. Accordingly, the ability to obtain the desired concentration of the active ingredient in the aqueous solution to be lyophilized is highly important, since one requires the desired weight of active ingredient in the end use container.
The solubility of vancomycin hydrochloride in water at room temperature is about 200 mg/ml. However, solutions containing vancomycin hydrochloride at a concentration of about 11 to about 12%, weight/volume, and higher have a high tendency to form gels. This gel formation results in severe handling problems. Further, when lyophilization is complete the vancomycin hydrochloride is obtained in the form of a dry plug which may dissolve slowly rather than as an easily soluble, flowable powder.
The gel formation appears to be a reversible process. Gel solutions can be restored to their original viscosity by pH adjustment. These aqueous gels apparently result from molecular associations which form non-covalently bonded polymeric structures.
This invention provides stable, gel-free concentrated aqueous solutions of vancomycin hydrochloride and a process for preparing vancomycin hydrochloride as a dry soluble, free-flowing powder from the concentrated solutions.